Abstract
RSR13 (2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylproprionic acid) is a synthetic allosteric modifier of oxygen (O2)-hemoglobin affinity that increases O2release to tissue by allosterically stabilizing deoxyhemoglobin. We tested the hypothesis that RSR13 enhances the functional recovery of stunned myocardium in barbiturate-anesthetized dogs instrumented for measurement of left ventricular (LV) and aortic blood pressure, LV +dP/dtmax and subendocardial segment shortening (%SS) in ischemic [left anterior descending (LAD) coronary artery] and normal (left circumflex coronary artery) zones. The partial pressure of oxygen and the Hill coefficient at 50% saturation (P50 and n50, respectively) were determined in arterial blood samples by multiple point tonometry and nonlinear regression analysis. Coronary collateral blood flow in the LAD zone was quantified with radioactive microspheres. Dogs received intravenous vehicle (0.45% saline) or one of two doses of RSR13 (100 or 150 mg·kg−1bolus followed by a 0.50 or 0.75 mg·kg−1·min−1infusion, respectively) in a random manner. All dogs were subjected to five 5-min periods of LAD occlusion separated by 5-min periods of reperfusion and followed by 180 min of final reperfusion during which hemodynamics, %SS, arterial blood gases, P50 andn50 were determined at selected intervals. RSR13 caused no hemodynamic effects and coronary collateral blood flow was equivalent among groups. RSR13 increased P50 (+40 ± 4% for the high dose) and decreased n50(−31 ± 2% for the high dose). LAD occlusion caused regional dyskinesia during each 5-min occlusion. Enhanced recovery of %SS by 180 min after final reperfusion was observed in dogs treated with high-dose RSR13 (47 ± 9% of base line) but not low-dose RSR13 (10 ± 18% of base line) or vehicle alone (2 ± 16% of base line). The results suggest that high-dose RSR13 improves the recovery of stunned myocardium throughout reperfusion in open-chest dogs. These findings may be related to increases in O2 availability to ischemic myocardium resulting from RSR13-induced stabilization of the deoxy form of hemoglobin.
Footnotes
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Send reprint requests to: Paul S. Pagel MD PhD, Medical College of Wisconsin, MEB - Room 462C, 8701 Watertown Plank Road, Milwaukee, WI 53226.
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↵1 This work was supported by a grant from the Foundation for Anesthesia Education and Research (J.R.K.), US PHS grants RO1HL54820 (D.C.W.), KO8HL03690 (J.R.K.), and GM08377 (D.C.W.), and a grant from Allos Therapeutics.
- Abbreviations:
- EDL
- end-diastolic segment length
- ESL
- end-systolic segment length
- %SS
- percent segment shortening
- LV
- left ventricle
- P50
- partial pressure of oxygen at 50% hemoglobin saturation
- n50
- Hill coefficient at 50% hemoglobin saturation
- PO2
- partial pressure of oxygen
- PCO2
- partial pressure of carbon dioxide
- +dP/dtmax
- maximum rate of increase of left ventricular pressure
- LAD
- left anterior descending coronary artery
- LCCA
- left circumflex coronary artery
- Received August 25, 1997.
- Accepted December 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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